Overexpression of insulin receptor substrate-1 emerges early in hepatocarcinogenesis and elicits preneoplastic hepatic glycogenosis.
Insulin receptor substrate-1 (IRS-1) is a multisite docking protein occupying a central position in signaling cascades stimulated by a number of growth factors including insulin. Using Western blotting and immunohistochemistry, we investigated the expression of IRS-1 in more than 400 preneoplastic foci of altered hepatocytes and in 12 hepatocellular carcinomas induced in rats by oral administration of N-nitrosomorpholine. In both N-nitrosomorpholine-treated and untreated rat livers, IRS-1 was demonstrable by Western blotting, but with the exception of a few single hepatocytes it was not detectable in the normal parenchyma by immunohistochemistry. In contrast, immunohistochemistry revealed that IRS-1 was strongly expressed in the majority of foci of altered hepatocytes particularly in approximately 97% of the clear/acidophilic and mixed cell foci showing excessive storage of glycogen (glycogenosis). In glycogen-poor basophilic foci of altered hepatocytes and hepatocellular carcinomas, IRS-1 was not detected by immunohistochemistry, but a weak expression was observed in small subpopulations of three hepatocellular carcinomas containing remnants of glycogen. These results indicate that the focal overexpression of IRS-1 is an early event in hepatocarcinogenesis, which is closely correlated with preneoplastic hepatic glycogenosis. During progression from glycogenotic foci to hepatocellular carcinomas, IRS-1-overexpression is gradually down-regulated, and this late event is associated with a fundamental metabolic shift leading to the malignant neoplastic phenotype.
Nehrbass
D
D
Abteilung für Cytopathologie, Deutsches Krebsforschungszentrum Im Neuenheimer Feld, Heidelberg, Germany.
Klimek
F
F
Bannasch
P
P
D000818:Animals; D002277:Carcinoma / Q000378:metabolism*; D006008:Glycogen Storage Disease / Q000378:metabolism*; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins